The present invention relates to an improved catalytic process for asymmetric hydrogenation. In particular, the present invention relates to a process for preparing intermediates useful in the synthesis of peripherally-selective inhibitors of dopamine-β-hydroxylase (DβH), the process involving catalytic asymmetric hydrogenation.
(R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (the compound of formula P, below) is a potent, non-toxic and peripherally selective inhibitor of DβH, which can be used for treatment of certain cardiovascular disorders. Compound P is disclosed in WO 2004/033447, along with processes for its preparation.

The process disclosed in WO 2004/033447 involves the reaction of (R)-6,8-difluorochroman-3-ylamine hydrochloride (the structure of (R)-6,8-difluorochroman-3-ylamine is shown below as compound Q), [4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl ester and potassium thiocyanate.

(R)-6,8-difluorochroman-3-ylamine (compound Q) is a key intermediate in the synthesis of compound P. The stereochemistry at the carbon atom to which the amine is attached gives rise to the stereochemistry of compound P, so it is advantageous that compound Q is present in as pure a form as possible. In other words, the R enantiomer of compound Q should be in predominance, with little or no S enantiomer present. Thus, the process for preparing compound Q will advantageously produce compound Q with as high an enantiomeric excess (ee) as possible.
An advantageous process for preparing a precursor of, for example, the compound of formula Q has now been found. The process involves catalytic asymmetric hydrogenation of a corresponding novel ene-carbamate. The process may also be employed in the preparation of similar precursors useful in the production of other peripherally-selective inhibitors of dopamine-β-hydroxylase.
The hydrogenation of ene-carbamates using Ru-BINAP and Ru-DuPhos catalysts is described in Dupau, P.; Bruneau, C.; Dixneuf, P. H. Tet. Asymm. 1999, 10, 3467-3471; and in Dupau, P.; Hay, A.-E.; Bruneau, C.; Dixneuf, P. H. Tet. Asymm. 2001, 12, 863. The maximum ee's obtained with either system are up to 76 (92 for one particular substrate), using a substrate/catalyst ratio of 100/1 and a hydrogen pressure of 100 bar.